Nearly 1 in 10 Americans over 12 years of age takes antidepressant medication, yet we know little about the neural basis for their disorder or the mechanism of their recovery. Recent work suggests that some of the cellular processes involved in learning and memory may also underlie depression, leading to the theory that depression arises from changes in neuronal plasticity that favor learning of the depressed state. The hippocampus is essential for the formation of new memories and its role in learning and memory is supported by a unique population of neurons that are constantly generated and replaced during adult life. As these adult- born neurons become integrated into the local network, they show increased plasticity to stimulation and are more likely to be incorporated into neural circuits during learning than existing hippocampal neurons. We believe that enhanced plasticity of these adult-born hippocampal neurons also contributes to pathological conditions such as depression, yet can likewise aid recovery during antidepressant treatment. Supporting this idea, recent experiments suggest that loss of adult neurogenesis prevents the onset of social avoidance following chronic stress, and conversely, blunts the behavioral response to antidepressant medications such as Prozac. The most common means of testing the role of adult neurogenesis in depression and recovery is to kill the dividing progenitors. Unfortunately, this produces an artificial setting in which to study the outcome, as the brain is highly plastic ad may accommodate for the loss of one neuronal population with another. A better solution would allow the adult-born neurons to integrate normally and then acutely prevent them from participating in the local circuit. We have developed a novel transgenic mouse model in which we can specifically and reversibly silence the activity of any population of neurons that can be genetically defined with a selective promoter. We provide preliminary data showing characterization of the new model and describe the next steps needed to optimize the system for selective silencing of adult-born hippocampal neurons. We then propose experiments using the new silencer system to test two hypotheses - first that the functional plasticity of adult-born neurons is necessary to induce the depressed state during chronic stress, and second that activity within these neurons is also necessary to recover from the depressed state during antidepressant treatment. We will test these hypotheses by suppressing activity in adult-born neurons during exposure to chronic stress, and during antidepressant treatment following induction of the depressed state. Our strategy will allow us to examine the function of adult-born neurons without destroying them, with the goal of more precisely defining the relationship between neurogenesis, depression, and therapeutic recovery.